Efficacy of HER2-Targeted Intraperitoneal 225Ac α-Pretargeted Radioimmunotherapy for Small-Volume Ovarian Peritoneal Carcinomatosis.

Epithelial ovarian cancer (EOC) is often asymptomatic and presents clinically in an advanced stage as widespread peritoneal microscopic disease that is generally considered to be surgically incurable. Targeted α-therapy with the α-particle-emitting radionuclide 225Ac (half-life, 9.92 d) is a high-linear-energy-transfer treatment approach effective for small-volume disease and even single cells. Here, we report the use of human epidermal growth factor receptor 2 (HER2) 225Ac-pretargeted radioimmunotherapy (PRIT) to treat a mouse model of human EOC SKOV3 xenografts growing as peritoneal carcinomatosis (PC). Methods: On day 0, 105 SKOV3 cells transduced with a luciferase reporter gene were implanted intraperitoneally in nude mice, and tumor engraftment was verified by bioluminescent imaging (BLI). On day 15, treatment was started using 1 or 2 cycles of 3-step anti-HER2 225Ac-PRIT (37 kBq/cycle as 225Ac-Proteus DOTA), separated by a 1-wk interval. Efficacy and toxicity were monitored for up to 154 d. Results: Untreated PC-tumor-bearing nude mice showed a median survival of 112 d. We used 2 independent measures of response to evaluate the efficacy of 225Ac-PRIT. First, a greater proportion of the treated mice (9/10 1-cycle and 8/10 2-cycle; total, 17/20; 85%) survived long-term compared with controls (9/27, 33%), and significantly prolonged survival was documented (log-rank [Mantel-Cox] P = 0.0042). Second, using BLI, a significant difference in the integrated BLI signal area to 98 d was noted between controls and treated groups (P = 0.0354). Of a total of 8 mice from the 2-cycle treatment group (74 kBq total) that were evaluated by necropsy, kidney radiotoxicity was mild and did not manifest itself clinically (normal serum blood urea nitrogen and creatinine). Dosimetry estimates (relative biological effectiveness-weighted dose, where relative biological effectiveness = 5) per 37 kBq administered for tumors and kidneys were 56.9 and 16.1 Gy, respectively. One-cycle and 2-cycle treatments were equally effective. With immunohistology, mild tubular changes attributable to α-toxicity were observed in both therapeutic groups. Conclusion: Treatment of EOC PC-tumor-bearing mice with anti-HER2 225Ac-PRIT resulted in histologic cures and prolonged survival with minimal toxicity. Targeted α-therapy using the anti-HER2 225Ac-PRIT system is a potential treatment for otherwise incurable EOC.

Pretargeting: A Path Forward for Radioimmunotherapy.

Pretargeted radioimmunodiagnosis and radioimmunotherapy aim to efficiently combine antitumor antibodies and medicinal radioisotopes for high-contrast imaging and high-therapeutic-index (TI) tumor targeting, respectively. As opposed to conventional radioimmunoconjugates, pretargeted approaches separate the tumor-targeting step from the payload step, thereby amplifying tumor uptake while reducing normal-tissue exposure. Alongside contrast and TI, critical parameters include antibody immunogenicity and specificity, availability of radioisotopes, and ease of use in the clinic. Each of the steps can be optimized separately; as modular systems, they can find broad applications irrespective of tumor target, tumor type, or radioisotopes. Although this versatility presents enormous opportunity, pretargeting is complex and presents unique challenges for clinical translation and optimal use in patients. The purpose of this article is to provide a brief historical perspective on the origins and development of pretargeting strategies in nuclear medicine, emphasizing 2 protein delivery systems that have been extensively evaluated (i.e., biotin-streptavidin and hapten-bispecific monoclonal antibodies), as well as radiohaptens and radioisotopes. We also highlight recent innovations, including pretargeting with bioorthogonal chemistry and novel protein vectors (such as self-assembling and disassembling proteins and Affibody molecules). We caution the reader that this is by no means a comprehensive review of the past 3 decades of pretargeted radioimmunodiagnosis and pretargeted radioimmunotherapy. But we do aim to highlight major developmental milestones and to identify benchmarks for success with regard to TI and toxicity in preclinical models and clinically. We believe this approach will lead to the identification of key obstacles to clinical success, revive interest in the utility of radiotheranostics applications, and guide development of the next generation of pretargeted theranostics.

Intraperitoneal Pretargeted Radioimmunotherapy for Colorectal Peritoneal Carcinomatosis.

Peritoneal carcinomatosis (PC) is considered incurable, and more effective therapies are needed. Herein we test the hypothesis that GPA33-directed intracompartmental pretargeted radioimmunotherapy (PRIT) can cure colorectal peritoneal carcinomatosis. Nude mice were implanted intraperitoneally with luciferase-transduced GPA33-expressing SW1222 cells for aggressive peritoneal carcinomatosis (e.g., resected tumor mass 0.369 ± 0.246 g; n = 17 on day 29). For GPA33-PRIT, we administered intraperitoneally a high-affinity anti-GPA33/anti-DOTA bispecific antibody (BsAb), followed by clearing agent (intravenous), and lutetium-177 (Lu-177) or yttrium-86 (Y-86) radiolabeled DOTA-radiohapten (intraperitoneal) for beta/gamma-emitter therapy and PET imaging, respectively. The DOTA-radiohaptens were prepared from S-2-(4-aminobenzyl)-1,4,7, 10-tetraazacyclododecane tetraacetic acid chelate (DOTA-Bn). Efficacy and toxicity of single- versus three-cycle therapy were evaluated in mice 26-27 days post-tumor implantation. Single-cycle treatment ([177Lu]LuDOTA-Bn 111 MBq; tumor dose: 4,992 cGy) significantly prolonged median survival (MS) approximately 2-fold to 84.5 days in comparison with controls (P = 0.007). With three-cycle therapy (once weekly, total 333 MBq; tumor dose: 14,975 cGy), 6/8 (75%) survived long-term (MS > 183 days). Furthermore, for these treated long-term survivors, 1 mouse was completely disease free (microscopic "cure") at necropsy; the others showed stabilized disease, which was detectable during PET-CT using [86Y]DOTA-Bn. Treatment controls had MS ranging from 42-52.5 days (P < 0.001) and 19/20 mice succumbed to progressive intraperitoneal disease by 69 days. Multi-cycle GPA33 DOTA-PRIT significantly prolongs survival with reversible myelosuppression and no chronic marrow (929 cGy to blood) or kidney (982 cGy) radiotoxicity, with therapeutic indices of 12 for blood and 12 for kidneys. MTD was not reached.

Learning curve of robot-assisted transabdominal preperitoneal (rTAPP) inguinal hernia repair: a cumulative sum (CUSUM) analysis.

BACKGROUND: Robot-assisted transabdominal preperitoneal inguinal hernia repair (rTAPP-IHR) is a safe and feasible approach for hernias of varying etiology. We aim to present a single surgeon's learning curve (LC) of this technique based on operative times, while accounting for bilaterality and complexity. METHODS: This is a retrospective cohort analysis of patients who underwent rTAPP-IHR over a period of 5 years. Patients who underwent primary, recurrent, and complex (previous posterior repair, previous prostatectomy, scrotal, incarcerated) repairs were included. Cumulative and risk-adjusted cumulative sum analyses (CUSUM and RA-CUSUM) were used to depict the evolution of skin-to-skin times and complications/surgical site events (SSEs) with time, respectively. RESULTS: A total of 371 patients were included in the study. Mean skin-to-skin times were stratified according to four subgroups: unilateral non-complex (46.8 min), unilateral complex (63.2 min), bilateral non-complex (70.9 min), and bilateral complex (102 min). A CUSUM-LC was then plotted using each procedures difference in operative time from its subgroup mean. The peak of the plot occurred at case number 138, which was used as a transition between 'early' and 'late' phases. The average operative time for the late phase was 15.9 min shorter than the early phase (p < 0.001). The RA-CUSUM, plotted using the weight of case complexity and unilateral/bilateral status, also showed decreasing SSE rates after the completion of 138 cases (early phase: 8.8% vs. late phase: 2.2%, p = 0.008). Overall complication rates did not differ significantly between the two phases. CONCLUSIONS: Our study shows that regardless of bilateral or complex status, rTAPP operative times and SSE rates gradually decreased after completing 138 procedures. Previous laparoscopic experience, robotic team efficiency, and surgical knowledge are important considerations for a surgeon's LC.

Paraconduit Hiatal Hernia Following Esophagectomy: Incidence, Risk Factors, Outcomes and Repair.

BACKGROUND: Paraconduit hiatal hernia (PCHH) is a known complication of esophagectomy with significant morbidity. PCHH may be more common with the transition to a minimally invasive approach and improved survival. We studied the PCHH occurrence following minimally invasive esophagectomy to determine the incidence, treatment, and associated risk factors. METHODS: We retrospectively reviewed records of patients who underwent esophagectomy at an academic tertiary care center between 2013-2020. We divided the cohort into those who did and did not develop PCHH, identifying differences in demographics, perioperative characteristics and outcomes. We present video of our laparoscopic repair with mesh. RESULTS: Of 49 patients who underwent esophagectomy, seven (14%) developed PCHH at a median of 186 d (60-350 d) postoperatively. They were younger (57 versus 64 y, P< 0.01), and in cases of resection for cancer, more likely to develop tumor recurrence (71% versus 23%, P= 0.02). There was a significant difference in 2-y cancer free survival of patients with a PCHH (PCHH 19% versus no hernia 73%, P< 0.01), but no significant difference in 5-y overall survival (PCHH 36% versus no hernia 68%, P= 0.18). Five of seven PCHH were symptomatic and addressed surgically. Four PCHH repairs recurred at a median of 409 d. CONCLUSIONS: PCHH is associated with younger age and tumor recurrence, but not mortality. Safe repair of PCHH can be performed laparoscopically with or without mesh. Further studies, including systematic video review, are needed to address modifiable risk factors and identify optimal techniques for durable repair of post-esophagectomy PCHH.

Hyperthyroidism Symptoms, Management, and Outcomes in Children and Adults Seeking Definitive Surgical Treatment.

OBJECTIVE: To identify the difference in presentation, time to treatment, and outcomes between hyperthyroid adults and children referred to surgical evaluation. BACKGROUND: There is little data on differences in presenting symptoms, time to treatment, and outcomes between adults and children presenting for thyroidectomy for Graves' disease. METHODS: We retrospectively reviewed records of patients with hyperthyroidism referred for thyroidectomy between January 2016 and April 2017. We divided our cohort into 2 groups based on age, children (age ≤18 years), and adults (age >18), and evaluated the difference in prevalence of symptoms, time from diagnosis, and initiation of antithyroid medications to surgery, and outcomes. RESULTS: We identified 38 patients (27 adults and 11 children) with data on hyperthyroidism symptoms referred for thyroidectomy. Relative to hyperthyroid adults, children with hyperthyroidism were more likely to present with hoarseness (55% vs 15%, P = 0.01) and difficulty concentrating (45% vs 7%, P = 0.01) at initial presentation. There was no statistically significant difference in prevalence of vision changes, exophthalmos, pretibial myxedema, palpitations, fatigue, temperature intolerance, dysphagia, tremors, or constitutional symptoms. A median of 15 months elapsed from diagnosis to thyroidectomy among adult and 6 months among pediatric patients. Adult and pediatric patients waited a median of 13 and 6 months from initiation of antithyroid medications to thyroidectomy, respectively. There was no significant difference in outcomes. CONCLUSIONS: Children with hyperthyroidism were more likely to present with hoarseness and difficulty concentrating than adults. Concentration and communication are critical skills in developing children, and early intervention with definitive therapy may improve such symptoms.

Learning Curve of Robotic Rives-Stoppa Ventral Hernia Repair: A Cumulative Sum Analysis.

Background: Robotic Rives-Stoppa ventral hernia repair (rRS-VHR) is a minimally invasive technique that incorporates extraperitoneal mesh placement, using either transabdominal or totally extraperitoneal access. An understanding of its learning curve and technical challenges may guide and encourage its adoption. We aim at evaluating the rRS-VHR learning curve based on operative times while accounting for adverse outcomes. Materials and Methods: We conducted a retrospective analysis of patients undergoing rRS repair for centrally located ventral and incisional hernias. A single surgeon operative time-based cumulative sum (CUSUM) analysis learning curve was created, and a composite outcome was used for risk-adjusted CUSUM (RA-CUSUM). Results: Eighty-one patients undergoing rRS-VHR were included. A learning curve was created by using skin-to-skin times. Accordingly, patients were grouped into three phases. The mean skin-to-skin time was 72.2 minutes, and there was a significant decrease in skin-to-skin times throughout the learning curve (Phase-I: 86.4 minutes versus Phase-III: 63.8 minutes; P = .001), with a gradual decrease after 29 cases. Eleven patients experienced adverse composite outcomes, which were used to create a RA-CUSUM graph. Results showed the highest adverse outcome rates in Phase-II, with a gradual decrease in risk-adjusted operative times after 51 cases. Conclusions: Consistently decreasing operative times and adverse outcome rates in rRS-VHR was observed after the completion of 29 and 51 cases, respectively. Future studies that provide group learning curves for this procedure can deliver more generalizable results in terms of its performance rates.

Learning Curve in Robotic Primary Ventral Hernia Repair Using Intraperitoneal Onlay Mesh: A Cumulative Sum Analysis.

BACKGROUND: Cumulative sum (CUSUM) learning curves (LCs) are useful to analyze individual performance and to evaluate the acquisition of new skills and the evolution of those skills as experience is accumulated. The purpose of this study is to present a CUSUM LC based on the operative times of robotic intraperitoneal onlay mesh (rIPOM) ventral hernia repair (VHR) and identify differences observed throughout its phases. MATERIALS AND METHODS: Patients who underwent rIPOM repair for elective, midline, and primary hernias were included. All procedures were performed exclusively by one surgeon within a 5-year period. CUSUM and risk-adjusted CUSUM were used to visualize the LC of rIPOM-VHR, based on operative times and complications. Once groups were obtained, univariate comparisons were performed. RESULTS: Of the 90 rIPOM repairs, 25, 40, and 25 patients were allocated using a CUSUM analysis to the early, middle, and late phases, respectively. In terms of skin-to-skin times, the middle phase has a mean duration of 23 minutes shorter than the early phase (P<0.001), and the late phase has a mean duration 34 minutes shorter than the early phase (P<0.001). A steep decrease in off-console time was observed, with a 10-minute difference from early to middle phases. A consistent and gradual decrease in operative times was observed after completion of 36 cases, and a risk-adjusted CUSUM revealed improving outcomes after 55 cases. CONCLUSIONS: This study demonstrates and elucidates interval improvement in operative efficiency in rIPOM-VHR. Consistently decreasing operative times and simultaneous accumulated complication rates were observed after the completion of 55 cases.

Health Literacy in Surgery.

BACKGROUND: Low health literacy is associated with poor health outcomes in many chronic diseases and may have an important role in determining surgical outcomes. This study aims to comprehensively review the current state of science on adult health literacy in surgery and to identify knowledge gaps for future research. METHODS: Using the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, a systematic search was conducted to identify all studies from January 2002 through May 2018 that used validated instruments to assess health literacy among adult patients undergoing surgery. Studies were assessed for quality using the Newcastle-Ottawa scale and evaluated on findings by their focus on identifying health literacy levels, understanding associations with surgical outcomes, and/or developing interventions to address low health literacy. KEY RESULTS: There were 51 studies on health literacy with data from 22,139 patients included in this review. Low health literacy was present in more than one-third of surgical patients (34%, interquartile range 16%-50%). The most commonly used validated instrument for assessment of health literacy in the surgical population was the Newest Vital Sign. Most studies were focused on identifying the prevalence of low health literacy within a surgery population (84%, n = 43). Few studies focused on understanding the association of health literacy to surgical outcomes (12%, n = 6) and even fewer studies developed interventions to address health literacy (4%, n = 2). DISCUSSION: Low health literacy is common among surgical patients. Important opportunities exist to better understand the role of health literacy in determining surgical outcomes and to develop more health literacy-sensitive models of surgical care. [HLRP: Health Literacy Research and Practice. 2020;4(1):e45-e65.] PLAIN LANGUAGE SUMMARY: Health literacy has not been well-studied in surgery but likely plays an important role. In this article, we reviewed all current research on health literacy in surgery to help us understand where we are at and where we need to go. We found that low health literacy is common and we need more ways to address it in surgery.

Impact of Preoperative Care for Rectal Adenocarcinoma on Pathologic Specimen Quality and Postoperative Morbidity: A NSQIP Analysis.

BACKGROUND: Comprehensive and multidisciplinary care are critical in rectal cancer treatment. We sought to determine if completeness of preoperative care was associated with pathologic specimen quality and postoperative morbidity. STUDY DESIGN: Clinical stage I-III rectal adenocarcinoma patients who underwent elective low anterior resection or abdominoperineal resection were identified from the 2016-2017 American College of Surgeons-National Surgical Quality Improvement Project (ACS-NSQIP) database. The 3 preoperative NSQIP variables (colonoscopy, stoma marking, and neoadjuvant chemoradiation) were used to divide patients into 2 cohorts: complete vs incomplete preoperative care. The primary outcome was a composite higher pathologic specimen quality score (>12 lymph nodes, negative circumferential, and negative distal margins). The secondary outcome was 30-day morbidity. Preoperative characteristics were compared with ANOVAs and chi-square tests. Outcomes measures were evaluated with logistic regression. RESULTS: We identified 1,125 patients: 591 (52.5%) complete and 534 (47.5%) incomplete. The complete group was younger, had more women, lower-third rectal tumors, clinical stage III disease, and neoadjuvant treatment. The complete group had higher odds of better pathologic specimen quality after adjusting for age, sex, tumor location, stage, and neoadjuvant therapy (adjusted odds ratio [aOR] 1.75, p = 0.001). The complete group had decreased rates of transfusions (odds ratio [OR] 0.47, p < 0.001), postoperative ileus (OR 0.67, p = 0.01), sepsis (OR 0.32, p = 0.01), and readmissions (OR 0.60, p = 0.003). Other complications did not statistically differ between groups. CONCLUSIONS: Complete preoperative care in rectal adenocarcinoma is associated with higher pathologic specimen quality and reduced postoperative morbidity. This highlights the importance of adherence to guideline-directed care.

Gender and Racial Disparities in Survival After Surgery Among Papillary and Patients With Follicular Thyroid Cancer: A 45-Year Experience.

BACKGROUND: Demographic disparities have been described for survival after thyroid cancer surgery using national registries and databases. At the institution level, we hypothesized that assessing survival after thyroid cancer surgery in a long-term cohort with diverse gender and racial groups would reveal disparities in survival. METHODS: We examined medical records of patients with papillary or follicular thyroid cancer undergoing thyroidectomy, lobectomy, and other surgical procedures from 1971 to 2016 at a tertiary referral center. We obtained information on demographics, cancer stage, procedure, and radioactive iodine (RAI). We measured survival using Kaplan-Meier estimates and Cox proportional hazards models. RESULTS: A total of 1440 (91%) patients with papillary cancer and 144 (9%) patients with follicular thyroid cancer underwent total thyroidectomy (1297, 82%), lobectomy (261, 16.5%), and other surgical procedures (26, 1.5%). Most patients (1131, 71%) were woman, and 909 (57%) were older than 45 years. Race/ethnicity included 805 (51%) white, 161 (10%) African Americans, and 618 (39%) other race/ethnicities. Both 10- and 20-year survival rates in nonwhite males were worse compared with nonwhite females (P < .0001). After controlling for age, cancer type, stage, surgical procedure, RAI, and year of surgery, nonwhite males had a higher mortality risk compared with nonwhite females (P = .0376, confidence interval (CI): 1.03-2.43), white males (P < .0001, CI: 1.88-6.54), and white females (P < .0001, CI: 3.31-9.90). CONCLUSIONS: Our diverse cohort demonstrates significant gender and racial disparities in survival after thyroid cancer surgery. To improve health outcomes and reduce health disparities among nonwhite males, interventions and long-term care management should target potentially modifiable causes of worse outcomes in this group.

Hyperthyroidism is Underdiagnosed and Undertreated in 3336 Patients: An Opportunity for Improvement and Intervention.

OBJECTIVE: The aim of this study was to determine the prevalence of undiagnosed and untreated hyperthyroidism among patients with suppressed thyroid-stimulating hormone (TSH). BACKGROUND: Hyperthyroidism can significantly diminish patient quality of life and increase the financial burden on patients and health systems. We hypothesized that many patients with hyperthyroidism remain undiagnosed because physicians fail to recognize and evaluate suppressed TSH as the first indication of disease. METHODS: We reviewed administrative data on 174011 patients with TSH measured at a tertiary referral center between 2011 and 2017 to identify individuals with hyperthyroidism (TSH <0.05 mU/L) and their subsequent outcomes: evaluation (measurement of T4, T3, radioactive iodine (RAI) uptake scan, thyroid-stimulating immunoglobulin, thyroid peroxidase antibodies) diagnosis, referral and treatment. We used Kaplan-Meier methods and multivariable time-related parametric hazard modeling to measure our outcomes. RESULTS: We found 3336 patients with hyperthyroidism. The mean age of our cohort was 52 ±â€Š17 years, with 79% females and 59% whites. Only 1088 patients (33%) received any appropriate evaluation and hyperthyroidism remained undiagnosed in 37% of patients who had the appropriate workup. Among those diagnosed with hyperthyroidism, only 21% were referred for surgery and 34% received RAI. Predictors for hyperthyroidism diagnosis include lower TSH (0.01u/L), younger age, African-American race, private commercial insurance, being seen in an outpatient setting, absence of medical comorbidities, presentation with ophthalmopathy, or weight loss. CONCLUSIONS: Hyperthyroidism is frequently unrecognized and untreated, which can lead to adverse outcomes and increased costs. Improved systems for detection and treatment of hyperthyroidism are needed to address this gap in care.